Healthy blood monocytes are immunologically quiescent cells. We found that monocytes isolated from the blood of SLE patients have dendritic cell (DC) function that could partially be ascribed to Type IIFN. Comparison of transcriptional patterns of healthy and SLE monocytes revealed the differential expression of 982 transcripts of which 1) 608 were due to Type I IFN exposure, 2) 116 could not be ascribed to Type I IFN but were also expressed in healthy blood myeloid DCs (mDCs), and 3) 258 were neither type I IFN nor mDCs genes which we call unique SLE monocytes transcription patterns. Thus, SLE monocytes carry type I IFN-related and unrelated transcriptional signatures which might reflect alterations in other blood cell compartments and provide explanation for altered B cell compartment. Therefore, we propose a hypothesis that SLE monocytes are central to etiopathogenesis of SLE. We have designed three aims to test our hypothesis: Aim 1 will identify markers of SLE monocytes that can be used in patients follow-up. Aim 2 will determine factors that trigger SLE monocytes transcription patterns. We will establish if cells (neutrophils or plasmacytoid DCs) and/or cell products (immune complexes) contribute to SLE monocytes phenotype and function. We will also assess therapeutic effect of ImmunoRegulatory ODN. Aim 3 will demonstrate that SLE monocytes activate B cells. Thus, the research plan that we propose here will generate: 1) markers for disease follow up and response to therapy;and 2) novel molecules relevant for disease pathogenesis and novel therapeutic targets.